Project Summary/Abstract Patients with end-stage renal disease (ESRD) receiving hemodialysis (HD) commonly experience chronic pain, resulting in a disproportionate number receiving long-term opioid therapy (LTOT). Due to the generally unfavorable risk-benefit profile of LTOT, current consensus guidelines promote 1) continuous re-assessment of benefit and risk of opioids and 2) reduction or discontinuation of LTOT while boosting pain self-management strategies and non-opioid pain care when benefit no longer outweighs harm. Research on optimal LTOT tapering strategies has lagged behind clinical need and patients on HD may be especially vulnerable to the problems resulting from clinical inertia. Our team has developed evidence-based interventions addressing clinical inertia in LTOT tapering. First, the Collaborative Opioid Reassessment Program (CORP) consists of a pharmacist-physician team that performs in-depth assessment and management of patients experiencing issues related to safety or efficacy or opioids, offering rotation to buprenorphine, a partial mu opioid receptor agonist, as a highly promising taper strategy. CORP can be delivered virtually using video-telehealth. Cooperative Pain Education and Self-Management (COPES) is a cognitive-behavioral therapy (CBT) program delivered via telehealth that improves pain interference, the consensus-recommended highest priority pain outcome measure. While CORP and COPES are established interventions, whether to provide rotation to buprenorphine to all patients as part of CORP (CORP-B) and whether all patients attempting a taper would benefit from COPES tailored for patients receiving HD (COPES-HD) are important unstudied questions, lending this work to a sequential, multiple assignment randomized trial (SMART) design that allows adaption of the intervention at critical decision points in a patient's care based on a priori response criteria. We propose to adapt CORP and COPES for patients receiving HD and LTOT and to test their effectiveness in a pragmatic randomized SMART. Initial randomization will be to compare CORP-supported taper with (CORP-B) and without (CORP) buprenorphine rotation on the 6-month composite outcome of LTOT dose reduction and pain response. Response to initial treatment will be assessed in weeks 3-8 post randomization; those who fail to meet a priori criteria for response will be immediately switched to the other arm and randomized to augmentation with COPES-HD or not, responders will remain on their initial treatment and be randomized to augmentation with COPES-HD or not. This innovative design will allow us to determine which of the eight adaptive treatment strategies leads to the greatest reduction in 6-month opioid dose and pain interference. The novel aspects of this proposal include: 1) the use of a SMART design, 2) the combination of a pain-focused pharmacist/physician team using telehealth and buprenorphine, 3) a test of CBT augmentation to opioid tapering, and 4) a pragmatic design. This study, conducted by a team of experienced pain, renal and addiction researchers, holds promise of identifying an effective strategy for addressing LTOT in patients receiving HD.